Laboratory of chemistry of nucleotides and polynucleotides

 

Head of Laboratory - Grigorij Gavrilovich Sivets
Doctor of Chemical Sciences
Laureate of State Prize of the Republic of Belarus
Laureate of the Prize of Council of Ministers of Latvian SSR

 

tel. +375 (17) 263-76-17
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About laboratory

It was created in October of 1973, as part of the Division of Bioorganic Chemistry of Institute of Physical Organic Chemistry of Belorussian Academy of Sciences. From January 1974 the laboratory became a member of the Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus. Laboratory was headed until 2003 by Corresponding Member of the National Academy of Sciences of Belarus, professor, Doctor of Chemical Sciences, laureate of State Prize of the Republic of Belarus, laureate of Prize of Council of Ministers of Latvian SSR Igor Alexandrovich Mikhailopulo. Since 2003 till 2011 the laboratory was headed by E.N. Kalinichenko, D.Sc.

The laboratory is accredited for compliance with СТБ ИСО/МЭК 17025 (General requirements for the competence of testing and calibration laboratories in Belarus, analogue of ISO/IEC 17025:2005)
Registration number of the certificate of accreditation BY/112 02.1.0.1683 от 08.11.2010 г.
Scope of accreditation: Finished medicinal products and pharmaceutical substances.

There are 15 employees in the laboratory, including 1 corresponding member, 4 PhDs, and 3 postgraduates.

The laboratory is the only science center in the country for systematic and comprehensive study of analogues of nucleic acids components.


The direction of research

  1. The synthesis of sugars, nucleosides, nucleotides and 2'-5'-oligoadenylates; the study of their stereochemistry, biological and biochemical properties, the elucidation of the dependencies between their stereochemistry and chemical or biological properties.
  2. The development of chemical-enzymatic methods of synthesis of analogues of natural nucleosides and nucleotides.
  3. The development of technologies for producing antiviral and anticancer drugs.


Major achievements

  1. The strategy of chemical-enzymatic synthesis of modified nucleosides and nucleotides has been formed. Search for new bioactive compounds has been carried out, the causation has been determined between structure, stereochemistry and biological activity of nucleosides, oligonucleotides.
  2. Highly efficient methods for creation analogues of nucleic acids components have been developed.
  3. Wide range of fluorodeoxysugars, of nucleosides, nucleotides and oligonucleotides has been obtained. Their stereochemical peculiarities which are important for the understanding of biochemical reactions and for creation of purposeful approach for designing drugs have been studied on the basis of conformational analysis.
  4. Peculiarities of the functioning of immune system cells and peculiarities of enzymes of exchange of nucleic acids which determine the metabolism of nucleosides in infected cells have been clarified.

Significant publications of recent years

  1. V.N.Barai, A.I.Zinchenko, L.A.Eroshevskaya, E.N.Kalinichenko, T.I.Kulak, I.A.Mikhailopulo. Anuniversal biocatalyst for the preparation of base and sugar modified nucleosides via an enzymatic transglycosylation // Helv. Chim. Acta. - 2002. - Vol. 85, N7. - P. 1901-1908.
  2. K.Krawiec, B.Kierdaszuk, E.N.Kalinichenko, E.B.Rubinova, I.A.Mikhailopulo, S.Eriksson, B.Munch-Petersen, D.Shugar. Striking Ability of Adenosine-2'(3')-deoxy-3'(2')-triphosphates, and Related Analgoues to Replace ATP as Phosphate Donor for all Four Human, and the Drosophila Melanogaster, Deoxyribonucleoside Kinase // Nucleosides Nucleotides. - 2003. - Vol. 22, N2. - P.153-173.
  3. I.A.Mikhailopulo, T.I.Pricota, G.G.Sivets, C.Altona. 2'-Chloro-2',3'-dideoxy-3'-fluoro-D-ribonucleosides: Synthesis, Stereospecificity, Some Chemical Transformations, and Conformational Analysis // J. Org. Chem. - 2003. - Vol. 68. - P. 5897-5908.
  4. E.N.Kalinichenko, T.L.Podkopaeva, E.V.Budko, F.Seela, B.Dong, R.Silverman, J.Vepsäläinen, P.F.Torrence, I.A.Mikhailopulo. 3-Deazaadenosine Analogues of p5'A2'p5'A2'p5'A: Synthesis, Stereochemistry, and the Roles of Adenine Ring Nitrogen-3 in the Interaction with RNase L // Bioorg. Med. Chem. - 2004. - Vol.12. - P. 3637-3647.
  5. G.G.Sivets, J.Vepsäläinen, I.A.Mikhailopulo. Synthesis of [2-O-(2-methoxyethyl)-ß-D-ribofuranosyl] purines using 1-methanesulfonyloxy-2-methoxyethane // Lett. Org. Chem. - 2005. - Vol.2, N4. - P. 343-348.
  6. J.J.Jr.Barchi, R.G.Karki, M.C.Nicklaus, M.A.Siddiqui, C.George, I.A.Mikhailopulo, V.E.Marquez. Comprehensive Structural Studies of 2',3'-Difluorinated Nucleosides: Comparison of Theory, Solution and Solid State // J. Am. Chem. Soc. - 2008. - Vol. 130, N28. - P. 8048-8057.
  7. G.G.Sivets, E.N.Kalinichenko, I.A.Mikhailopulo, M.A.Detorio, T.R.McBrayer, T.Whitaker, R.F.Schinazi. Synthesis and antiviral activity of purine 2',3'-dideoxy-2',3'-difluoro-D-arabinofuranosyl nucleosides // Nucleosides, Nucleotides Nucleic Acids. - 2009. - Vol. 28, N5-6. - P. 519-536.
  8. A.I.Miroshnikov, R.S.Esipov, T.I.Muravyova, I.D.Konstantinova, I.V.Fateev, I.A.Mikhailopulo. A new strategy for the synthesis of nucleosides: one-pot enzymatic transformation of D-pentoses into nucleosides // The Open Conf. Proc. J. – 2010. – Vol. 1. – P. 98-102.

Practical development

The technologies for creation of pharmaceutical substances of socially important onco-hematologic and antiviral drugs have been developed, and the permission for their industrial production and medical applications has been obtained. These are:

The production of the pharmaceutical substances Cytosorbine, Zamicit, Leucladine, Fludarabel has been organized at Self-supporting Pilot Enterprise of Institute of Bioorganic Chemistry. The production of dosage forms of drugs Cytarabine, Thioguanine, Phosphaden, Nucleovir, Cytosorbine, Zamicit has been organized at Republican Unitary Production Enterprise "Belmedpreparaty". The production of dosage forms of medicines Leucladine, Fludarabel has been organized jointly with Institute of Microbiology of National Academy of Science of Belarus.

The combined medication for treatment of multiple sclerosis – Leukovir is at the stage of clinical study and organization of production (in collaboration with Institute of Microbiology of National Academy of Science of Belarus).

Leykladin is registered in Russia (ЛСР 001440-09) and Kazakhstan (РК-ЛС-5-№016919, РК-ЛС-5-№016918). Leykladin is exported.

Fludarabel is registered in Azerbaijan (DV № 10-00222).

The registration process of medicines Leykladin, Fludarabel in Ukraine, Russia and Kazakhstan is in action.

There was the instruction of Prime Minister of Republic of Belarus S.S Sidorsky "...to develop our own technology and our own mass production of import-replacing products on a scale that will enable us to fully meet the needs of domestic medicine in modern onco-hematological and antiviral drugs, and also to carry out their export." An innovative project "Reconstruction of the premises of pilot production of IBOCH NAS of Belarus, building 'V', for creation the technology and for creation small-tonnage production of new pharmaceutical substances” in accordance with this instruction is being implemented. This project is included into State Program of Innovative Development of Republic of Belarus for 2007-2010, approved by Resolution of Council of Ministers from 25 April 2007 № 523 and by Decree of President of Republic Belarus from 16 October 2008 № 562.


The laboratory collaborates with the following overseas and Belorussian research centers

  1. University of Kuopio (Finland) Prof. A. Azhayev.
  2. Atlanta Research and Educational Foundation (Decatur, Georgia/Emory University, USA) Prof. R.F. Schinazi.
  3. Institute of Bioorganic Chemistry named after M.M.Shemyakin and Y.A.Ovchinnikov (Russian Academy of Sciences, Moscow), academician of RAS, A.I. Miroshnikov.
  4. University of Osnabrück (Germany), Prof. H. Rosemeyer.
  5. Institute of Microbiology of National Academy of Sciences of Belarus

 

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